We identify and topographically localize inflammatory, degenerative, and malignant cells, as well as their products and related molecules, in patient specimens and animal tissues. We analyze these cells and their products mainly by routine pathology, ultrastructure, immunohistochemistry, and molecular pathology. The application of cutting-edge technology, such as microdissection combined with molecular techniques (PCR, RT-PCR, genotyping, etc.) allows us to provide a more accurate pathological diagnosis (assessment) and a better understanding of the pathogenesis of the disease. These technologies and findings will guide us in selecting the most targeted treatments for patients. We also study the mechanisms of different ocular diseases from various animal models. Using animal models, we can assess the efficacy of novel therapeutic agents for various ocular diseases. In FY2015, we accomplished the following in our research: 1. Molecular Pathology of Age-Related Macular Degeneration (AMD): AMD is the leading cause of irreversible severe central vision loss among the elderly in the world. By 2050, the estimated number of people with late AMD is expected to increase from 2.07 million (as of 2010) to 5.4 million in the USA. The pathology of AMD is characterized by the accumulation of soft drusen, retinal pigment epithelium (RPE) and photoreceptor degeneration, geographic atrophy, and/or exudation with choroidal neovascularization in the macula. While several risk factors, including age, race, smoking, diet, oxidative stress and inflammation have been linked to AMD, the etiology and pathogenesis of the disease remain largely unclear. Current knowledge indicates that AMD development is strongly influenced by genetic factors. Treatment options exist for neovascular AMD include intravitreal injections of anti-vascular endothelial growth factor (VEGF); however, treatment options for geographic atrophy AMD are extremely limited. In FY2015, we reported the associations of new single nucleotide polymorphisms in RAD51B, FPR1 and UBE3D and AMD (see ZIA EY000418-12). We illustrated autophagosome formation, mitochondrial damage, the presence of extranuclear DNA, cytoplasmic pore formation, and NLRP inflammasome translocation in the RPE cells under inflammatory and/or oxidative stress, as well as in human eyes diagnosed with AMD. We suggest that one of the sources of AMD pathogenesis can be the activation of innate immunity resulting in damage to retinal tissue and cell death mediated by inflammatory cytokines (inflammasome IL1&#946;/IL18 IL17) and potentially caspase-1 mediated pyroptosis/necroptosis. 2. Ocular Lymphoma: Primary vitreoretinal lymphoma (PVRL), previously called primary intraocular lymphoma (PIOL), is a rare and fatal ocular malignancy. PVRL is mainly of B-cell origin wherein the cells infiltrate the eye and brain. The diagnosis of PVRL is often challenging as it can masquerade as chronic uveitis. We published and reviewed intraocular lymphoma models. Animal models aid in the study of lymphoma cell growth, as the malignant lymphocytes show little proliferative capacity in vitro. The animal models were used to show the efficacy to novel therapeutic agents, such as anti-B cell monoclonal antibodies. We also reported an unusual case of PVRL with renal, pelvic, and CNS lesions. 3. New Pathology and Pathogenesis of Ocular Diseases: We continue to study gender- and sex-based differences in infectious and noninfectious autoimmune uveitis. Male-predominant autoimmune diseases, such as Behets disease usually manifest clinically before the age of 50 and are characterized by acute inflammation and a Th1 response. HLA-B27 associated anterior uveitis in men is an example of this. Female-predominant autoimmunity, as found in rheumatoid arthritis and systemic lupus erythematosus tends to present later in life and likely occurs via Th2 and autoantibody related mechanisms. Recognition of the gender differences in autoimmunity, including uveitis, should allow new preventative and therapeutic strategies for patients in the future. We also illustrated unique and new molecular pathology in eyes with acute retinal necrosis as well as in von Hippel-Lindau disease with neovascularization of the iris and cornea, granulomatosis, with polyangitis. 4. Experimental animal models of ophthalmic diseases: As an editor, we invited 10 renown, visual scientists and ophthalmologist to co-author a book, which describes experimental animal models that mimic common human ocular diseases: herpetic keratitis, cataract, glaucoma, age-related macular degeneration, diabetic retinopathy, uveitis, retinitis pigmentosa, Graves disease, and intraocular tumors. In conjunction, these models reflect the diversity and utility of tools used to study human disease. World expert clinicians discuss each model based on their clinical experience. In describing the most pertinent animal models of ophthalmic diseases, this book will be of interest to ophthalmologists, vision researchers, fellows, residents, and medical students. This book will be published in 2015. We have shown progress in generation of a transgenic VHL mouse model with retinal hemangioblastoma. We used gene targeting technology and the cre-lox site-specific recombination system to generate this mouse model. Four years ago, we started out with mice with cre-recombinase gene fused with estrogen receptor under the control of an angioblast promotor (the SCL-Cre-ER(T)) and crossed with a mouse that has the VHL gene flanked by loxP sites. Then, we created a mouse in which when we give tamoxifen after E9.5 (at P16 day), where cre-recombinase can recognize the loxP sites and effectively delete the VHL gene. So here, we can induce the deletion of VHL past the time in development when it is embryonically lethal AND the angioblast promotor will give us cell specificity. The Immunopathology Section closed May 2015 with the retirement of Dr. Chan.